A phase III, multicentre, randomised, double-blind, active-controlled, parallel-group trial comparing safety and efficacy of HD203, with innovator etanercept, in combination with methotrexate, in patients with rheumatoid arthritis: the HERA study

Bae, Sang-Cheol,Kim, Jinseok,Choe, Jung-Yoon,Park, Won,Lee, Sang-Heon,Park, Yong-Beom,Shim, Seung-Cheol,Lee, Shin-Seok,Sung, Yoon-Kyoung,Choi, Chan-Bum,Lee, So-Ra,Park, HanYu,Ahn, Yongho H. K. Lewis 2017 Annals of the rheumatic diseases Vol.76 No.1

<P>Conclusion The study met the primary objective of demonstrating equivalent efficacy of HD203 and ETN. HD203 was well tolerated, with safety comparable with ETN in this population of patients with RA.</P>

Prophylactic effect of trimethoprim-sulfamethoxazole for pneumocystis pneumonia in patients with rheumatic diseases exposed to prolonged high-dose glucocorticoids

Park, Jun Won,Curtis, Jeffrey R,Moon, Jinyoung,Song, Yeong Wook,Kim, Suhnggwon,Lee, Eun Bong H. K. Lewis 2018 Annals of the rheumatic diseases Vol. No.

<P><B>Objectives</B></P><P>To investigate the efficacy and safety of trimethoprim/sulfamethoxazole (TMP-SMX) as primary prophylaxis for pneumocystis pneumonia (PCP) in patients with rheumatic diseases receiving high-dose steroids.</P><P><B>Methods</B></P><P>The study included 1522 treatment episodes with prolonged (≥4 weeks) high-dose (≥30 mg/day prednisone) steroids in 1092 patients over a 12-year period. Of these, 262 treatment episodes involved TMP-SMX (prophylaxis group) while other episodes involved no prophylaxis (control group). Differences in 1-year PCP incidence and its mortality between the two groups were estimated using Cox regression. To minimise baseline imbalance, propensity score matching was performed and efficacy outcome was mainly assessed in the postmatched population (n=235 in both groups).</P><P><B>Results</B></P><P>During a total of 1474.4 person-years, 30 PCP cases occurred with a mortality rate of 36.7%. One non-fatal case occurred in the prophylaxis group. TMP-SMX significantly reduced the 1-year PCP incidence (adjusted HR=0.07(95% CI 0.01 to 0.53)) and related mortality (adjusted HR=0.08 (95% CI 0.0006 to 0.71)) in the postmatched population. The result of the same analysis performed in the whole population was consistent with that of the primary analysis. Incidence rate of adverse drug reactions (ADR) related to TMP-SMX was 21.2 (14.8–29.3)/100 person-years. Only two serious ADRs (including one Stevens-Johnson syndrome case) occurred. The number needed to treat for preventing one PCP (52 (33–124)) was lower than the number needed to harm for serious ADR (131 (55–∞)).</P><P><B>Conclusion</B></P><P>TMP-SMX prophylaxis significantly reduces the PCP incidence with a favourable safety profile in patients with rheumatic disease receiving prolonged, high-dose steroids.</P>

Apolipoprotein B binds to enolase-1 and aggravates inflammation in rheumatoid arthritis

Lee, Joo Youn,Kang, Min Jueng,Choi, Ji Yong,Park, Ji Soo,Park, Jin Kyun,Lee, Eun Young,Lee, Eun Bong,Pap, Thomas,Yi, Eugene C,Song, Yeong Wook H. K. Lewis 2018 Annals of the rheumatic diseases Vol. No.

<P>Conclusions A key component of atherogenic lipids, apoB, aggravated arthritis by potentiating the inflammatory response via its interaction with ENO1 expressed on the surface of immune cells. This suggests a novel mechanism by which lipid metabolism regulates chronic inflammation in RA.</P>

Decreased <i>SMG7</i> expression associates with lupus-risk variants and elevated antinuclear antibody production

Deng, Yun,Zhao, Jian,Sakurai, Daisuke,Sestak, Andrea L,Osadchiy, Vadim,Langefeld, Carl D,Kaufman, Kenneth M,Kelly, Jennifer A,James, Judith A,Petri, Michelle A,Bae, Sang-Cheol,Alarcó,n-Riquelme, H. K. Lewis 2016 Annals of the rheumatic diseases Vol.75 No.11

<B>Objectives</B><P>Following up the systemic lupus erythematosus (SLE) genome-wide association studies (GWAS) identification of <I>NMNAT2</I> at rs2022013, we fine-mapped its 150 kb flanking regions containing <I>NMNAT2</I> and <I>SMG7</I> in a 15 292 case-control multi-ancestry population and tested functions of identified variants.</P><B>Methods</B><P>We performed genotyping using custom array, imputation by IMPUTE 2.1.2 and allele specific functions using quantitative real-time PCR and luciferase reporter transfections. SLE peripheral blood mononuclear cells (PBMCs) were cultured with small interfering RNAs to measure antinuclear antibody (ANA) and cyto/chemokine levels in supernatants using ELISA.</P><B>Results</B><P>We confirmed association at <I>NMNAT2</I> in European American (EA) and Amerindian/Hispanic ancestries, and identified independent signal at <I>SMG7</I> tagged by rs2702178 in EA only (p=2.4×10<SUP>−8</SUP>, OR=1.23 (95% CI 1.14 to 1.32)). In complete linkage disequilibrium with rs2702178, rs2275675 in the promoter region robustly associated with <I>SMG7</I> mRNA levels in multiple expression quantitative trait locus (eQTL) datasets. Its risk allele was dose-dependently associated with decreased <I>SMG7</I> mRNA levels in PBMCs of 86 patients with SLE and 119 controls (p=1.1×10<SUP>−3</SUP> and 6.8×10<SUP>−8</SUP>, respectively) and conferred reduced transcription activity in transfected HEK-293 (human embryonic kidney cell line) and Raji cells (p=0.0035 and 0.0037, respectively). As a critical component in the nonsense-mediated mRNA decay pathway, SMG7 could regulate autoantigens including ribonucleoprotein (RNP) and Smith (Sm). We showed <I>SMG7</I> mRNA levels in PBMCs correlated inversely with ANA titres of patients with SLE (r=−0.31, p=0.01), and <I>SMG7</I> knockdown increased levels of ANA IgG and chemokine (C-C motif) ligand 19 in SLE PBMCs (p=2.0×10<SUP>−5</SUP> and 2.0×10<SUP>−4</SUP>, respectively).</P><B>Conclusion</B><P>We confirmed <I>NMNAT2</I> and identified independent <I>SMG7</I> association with SLE. The inverse relationship between levels of the risk allele-associated <I>SMG7</I> mRNAs and ANA suggested the novel contribution of mRNA surveillance pathway to SLE pathogenesis.</P>

Maintenance of remission following 2 years of standard treatment then dose reduction with abatacept in patients with early rheumatoid arthritis and poor prognosis

Westhovens, Rene,Robles, Manuel,Ximenes, Antonio Carlos,Wollenhaupt, Jurgen,Durez, Patrick,Gomez-Reino, Juan,Grassi, Walter,Haraoui, Boulos,Shergy, William,Park, Sung-Hwan,Genant, Harry,Peterfy, Charl H. K. Lewis 2015 Annals of the rheumatic diseases Vol.74 No.3

<P><B>Objectives</B></P><P>To evaluate maintenance of response while reducing intravenous abatacept dose from ∼10 mg/kg to ∼5 mg/kg in patients with early rheumatoid arthritis (RA) who achieved disease activity score (DAS)28 (erythrocyte sedimentation rate, ESR) <2.6.</P><P><B>Methods</B></P><P>This 1-year, multinational, randomised, double-blind substudy evaluated the efficacy and safety of ∼10 mg/kg and ∼5 mg/kg abatacept in patients with early RA with poor prognosis who had reached DAS28 (ESR) <2.6 at year 2 of the AGREE study. The primary outcome was time to disease relapse (defined as additional disease-modifying antirheumatic drugs, ≥2 courses high-dose steroids, return to open-label abatacept ∼10 mg/kg, or DAS28 (C reactive protein) ≥3.2 at two consecutive visits).</P><P><B>Results</B></P><P>108 patients were randomised (∼10 mg/kg, n=58; ∼5 mg/kg, n=50). Three and five patients, respectively, discontinued, and four per group returned to open-label abatacept. Relapse over time and the proportion of patients relapsing were similar in both groups (31% (∼10 mg/kg) vs 34% (∼5 mg/kg); HR: 0.87 (95% CI 0.45 to 1.69)). Mean steady-state trough serum concentration for the ∼10 mg/kg group was 20.3–24.1 µg/mL, compared with 8.8–12.0 µg/mL for the ∼5 mg/kg group.</P><P><B>Conclusions</B></P><P>This exploratory study suggests that abatacept dose reduction may be an option in patients with poor prognosis early RA who achieve DAS28 (ESR) <2.6 after ≥1 year on abatacept (∼10 mg/kg).</P><P><B>Trial registration number</B></P><P>NCT00989235.</P>

Efficacy and safety of infliximab plus naproxen versus naproxen alone in patients with early, active axial spondyloarthritis: results from the double-blind, placebo-controlled INFAST study, Part 1

Sieper, J,Lenaerts, J,Wollenhaupt, J,Rudwaleit, M,Mazurov, V I,Myasoutova, L,Park, S,Song, Y,Yao, R,Chitkara, D,Vastesaeger, N H. K. Lewis 2014 Annals of the rheumatic diseases Vol.73 No.1

<P><B>Objectives</B></P><P>To assess whether combination therapy with infliximab (IFX) plus nonsteroidal anti-inflammatory drugs (NSAIDs) is superior to NSAID monotherapy for reaching Assessment of SpondyloArthritis international Society (ASAS) partial remission in patients with early, active axial spondyloarthritis (SpA) who were naïve to NSAIDs or received a submaximal dose of NSAIDs.</P><P><B>Methods</B></P><P>Patients were randomised (2 : 1 ratio) to receive naproxen (NPX) 1000 mg daily plus either IFX 5 mg/kg or placebo (PBO) at weeks 0, 2, 6, 12, 18 and 24. The primary efficacy measure was the percentage of patients who met ASAS partial remission criteria at week 28. Several other measures of disease activity, clinical symptoms and patient-rated outcomes were evaluated. Treatment group differences were analysed with Fisher exact tests or analysis of covariance.</P><P><B>Results</B></P><P>A greater percentage of patients achieved ASAS partial remission in the IFX+NPX group (61.9%; 65/105) than in the PBO+NPX group (35.3%; 18/51) at week 28 (p=0.002) and at all other visits (p<0.05, all comparisons). Results of most other disease activity and patient-reported endpoints (including Ankylosing Spondylitis Disease Activity Score, Bath Ankylosing Spondylitis Disease Activity Index, Bath Ankylosing Spondylitis Functional Index, multiple quality of life measures and pain measures) showed greater improvement in the IFX+NPX group than the PBO+NPX group, with several measures demonstrating early and consistent improvement over 28 weeks of treatment.</P><P><B>Conclusions</B></P><P>Patients with early, active axial SpA who received IFX+NPX combination treatment were twice as likely to achieve clinical remission as patients who received NPX alone. NPX alone led to clinical remission in a third of patients.</P>

Maintenance of biologic-free remission with naproxen or no treatment in patients with early, active axial spondyloarthritis: results from a 6-month, randomised, open-label follow-up study, INFAST Part 2

Sieper, J,Lenaerts, J,Wollenhaupt, J,Rudwaleit, M,Mazurov, V I,Myasoutova, L,Park, S,Song, Y,Yao, R,Chitkara, D,Vastesaeger, N H. K. Lewis 2014 Annals of the rheumatic diseases Vol.73 No.1

<P><B>Objective</B></P><P>To investigate whether biologic-free remission can be achieved in patients with early, active axial spondyloarthritis (SpA) who were in partial remission after 28 weeks of infliximab (IFX)+naproxen (NPX) or placebo (PBO)+NPX treatment and whether treatment with NPX was superior to no treatment to maintain disease control.</P><P><B>Method</B></P><P>Infliximab as First-Line Therapy in Patients with Early Active Axial Spondyloarthritis Trial (INFAST) Part 1 was a double-blind, randomised, controlled trial in biologic-naïve patients with early, active, moderate-to-severe axial SpA treated with either IFX 5 mg/kg+NPX 1000 mg/d or PBO+NPX 1000 mg/d for 28 weeks. Patients achieving Assessment of SpondyloArthritis international Society (ASAS) partial remission at week 28 continued to Part 2 and were randomised (1:1) to NPX or no treatment until week 52. Treatment group differences in ASAS partial remission and other efficacy variables were assessed through week 52 with Fisher exact tests.</P><P><B>Results</B></P><P>At week 52, similar percentages of patients in the NPX group (47.5%, 19/40) and the no-treatment group (40.0%, 16/40) maintained partial remission, p=0.65. Median duration of partial remission was 23 weeks in the NPX group and 12.6 weeks in the no-treatment group (p=0.38). Mean Bath Ankylosing Spondylitis Disease Activity Index scores were low at week 28, the start of follow-up treatment (NPX, 0.7; no treatment, 0.6), and remained low at week 52 (NPX, 1.2; no treatment, 1.7).</P><P><B>Conclusions</B></P><P>In axial SpA patients who reached partial remission after treatment with either IFX+NPX or NPX alone, disease activity remained low, and about half of patients remained in remission during 6 months in which NPX was continued or all treatments were stopped.</P>

2016 American College of Rheumatology/European League Against Rheumatism criteria for minimal, moderate, and major clinical response in adult dermatomyositis and polymyositis : An International Myositis Assessment and Clinical Studies Group/Paediatric Rh

Aggarwal, Rohit,Rider, Lisa G,Ruperto, Nicolino,Bayat, Nastaran,Erman, Brian,Feldman, Brian M,Oddis, Chester V,Amato, Anthony A,Chinoy, Hector,Cooper, Robert G,Dastmalchi, Maryam,Fiorentino, David,Ise H. K. Lewis 2017 Annals of the rheumatic diseases Vol.76 No.5

<P>To develop response criteria for adult dermatomyositis (DM) and polymyositis (PM). Expert surveys, logistic regression, and conjoint analysis were used to develop 287 definitions using core set measures. Myositis experts rated greater improvement among multiple pairwise scenarios in conjoint analysis surveys, where different levels of improvement in 2 core set measures were presented. The PAPRIKA (Potentially All Pairwise Rankings of All Possible Alternatives) method determined the relative weights of core set measures and conjoint analysis definitions. The performance characteristics of the definitions were evaluated on patient profiles using expert consensus (gold standard) and were validated using data from a clinical trial. The nominal group technique was used to reach consensus. Consensus was reached for a conjoint analysis-based continuous model using absolute per cent change in core set measures (physician, patient, and extramuscular global activity, muscle strength, Health Assessment Questionnaire, and muscle enzyme levels). A total improvement score (range 0-100), determined by summing scores for each core set measure, was based on improvement in and relative weight of each core set measure. Thresholds for minimal, moderate, and major improvement were >= 20, >= 40, and >= 60 points in the total improvement score. The same criteria were chosen for juvenile DM, with different improvement thresholds. Sensitivity and specificity in DM/ PM patient cohorts were 85% and 92%, 90% and 96%, and 92% and 98% for minimal, moderate, and major improvement, respectively. Definitions were validated in the clinical trial analysis for differentiating the physician rating of improvement (p< 0.001). The response criteria for adult DM/ PM consisted of the conjoint analysis model based on absolute per cent change in 6 core set measures, with thresholds for minimal, moderate, and major improvement.</P>

IL-32, a novel cytokine with a possible role in disease.

Dinarello, C A,Kim, S-H H. K. Lewis 2006 Annals of the rheumatic diseases Vol.65//SUP3 No.-

<P>IL-32 is the name given to the NK4 transcript first reported in IL-2 activated T lymphocytes and natural killer cells 13 years ago without known function. The novel cytokine has six isoforms. In an study to isolate a soluble form of the IL-32 receptor from human urine, IL-32alpha bound proteinase-3 with high affinity and was not affected by enzyme inhibition. IL-32alpha/IL-32gamma were expressed as recombinant molecules. The cytokine exhibits properties characteristic of proinflammatory cytokines and also induces the degradation of inhibitory kappaB and phosphorylation of mitogen activated protein p38. Monoclonal antibodies to IL-32 identify its presence in a variety of human tissues from diseases states. Epithelial cells from healthy subjects express low levels of the cytokine, but in disease conditions such as chronic obstructive pulmonary disease, Crohn's disease and psoriasis, the expression increases markedly. IL-32 is a major transcript in gene array studies in epithelial cells stimulated with IFNgamma in vitro. In rheumatoid arthritis, synovial tissues reveals increased content of IL-32, which correlates with severity of disease. A highly significant correlation has been observed between the number of synovial and macrophagic cells positive for IL-32 and the level of erythrocytes sedimentation, IL-1beta, tumour necrosis factor alpha, and IL-18. Thus, IL-32 exhibits many properties of proinflammatory cytokines and associations with disease severity.</P>

A multicentre randomised controlled trial to compare the pharmacokinetics, efficacy and safety of CT-P10 and innovator rituximab in patients with rheumatoid arthritis

Yoo, Dae Hyun,Suh, Chang-Hee,Shim, Seung Cheol,Jeka, Slawomir,Cons-Molina, Francisco Fidencio,Hrycaj, Pawel,Wiland, Piotr,Lee, Eun Young,Medina-Rodriguez, Francisco G,Shesternya, Pavel,Radominski, Seb H. K. Lewis 2017 Annals of the rheumatic diseases Vol.76 No.3

<P><B>Objective</B></P><P>To demonstrate pharmacokinetic equivalence of CT-P10 and innovator rituximab (RTX) in patients with rheumatoid arthritis (RA) with inadequate responses or intolerances to antitumour necrosis factor agents.</P><P><B>Methods</B></P><P>In this randomised phase I trial, patients with active RA were randomly assigned (2:1) to receive 1000 mg CT-P10 or RTX at weeks 0 and 2 (alongside continued methotrexate therapy). Primary endpoints were area under the serum concentration–time curve from time zero to last quantifiable concentration (AUC<SUB>0–last</SUB>) and maximum serum concentration after second infusion (C<SUB>max</SUB>). Additional pharmacokinetic parameters, efficacy, pharmacodynamics, immunogenicity and safety were also assessed. Data are reported up to week 24.</P><P><B>Results</B></P><P>103 patients were assigned to CT-P10 and 51 to RTX. The 90% CIs for the ratio of geometric means (CT-P10/RTX) for both primary endpoints were within the bioequivalence range of 80%–125% (AUC<SUB>0–last</SUB>: 97.7% (90% CI 89.2% to 107.0%); C<SUB>max</SUB>: 97.6% (90% CI 92.0% to 103.5%)). Pharmacodynamics and efficacy were comparable between groups. Antidrug antibodies were detected in 17.6% of patients in each group at week 24. CT-P10 and RTX displayed similar safety profiles.</P><P><B>Conclusions</B></P><P>CT-P10 and RTX demonstrated equivalent pharmacokinetics and comparable efficacy, pharmacodynamics, immunogenicity and safety.</P><P><B>Trial registration number</B></P><P>NCT01534884.</P>